ABSTRACT Outbreaks of HIV and HCV in rural areas of the Midwest have been associated with syringe-sharing among partners injecting nonmedical prescription opioids. Illinois ranks as the third highest state in percentage increase in death rates involving synthetic opiates between 2014-2015. The southernmost 16 counties of Illinois comprise the Illinois Delta Region (IDR) and share many of the characteristics of rural areas that have experienced recent HIV epidemics. A deeper understanding of community characteristics, including transitions from oral to injection opioid use, circumstances for high-risk injection practices, and accessibility to existing and potential health-related resources will be essential to developing models of disease prevention and treatment. Partnering with state and local public health other state agencies, community based programs, local coalitions and healthcare systems, we will take a mixed analytical approach using predictive modeling, GIS analysis, qualitative and survey analysis, network methods, and infectious disease epidemiology to understand geospatial and sociocultural factors impacting health outcomes in people who inject drugs in the IDR. These data will inform evidence-based interventions to strengthen access to disease screening and linkage to care and treatment, expansion of needle exchange and naloxone overdose programs, screening and referral to substance use treatment, and telehealth capacity building for the provision of PrEP, HCV management, and medication-assisted treatment for substance use disorder. UG3 Aim 1. Determine the geographic areas in the rural Illinois Delta Region at greatest risk for opioid misuse and infectious diseases in the IDR based on disease surveillance, healthcare utilization, prescription drug monitoring, arrest and drug seizure, and resource scarcity mapping. UG3 Aim 2. Understand how sociocultural factors impact risk and health seeking behaviors, social networks, and disease transmission of people who inject drugs in high risk geographic areas identified in Aim 1. UG3 Aim 3. Integrate and apply the epidemiological, geospatial, qualitative and network data to inform expanded harm-reduction services and targeted telehealth capacity building for related clinical care. UH3 Aim 1. Expand harm reduction services including syringe services, naloxone overdose prevention, substance use treatment referral, HIV, HCV, HBV and STDs testing and linkage to care through capacity building of existing programs as well as through new local health department based harm reduction units. UH3 Aim 2. Build capacity for HCV management, PrEP, substance use screening, referral, and medication- assisted treatment through telehealth programs targeted at PWID-preferred settings. UH3 Aim 3. Evaluate program implementation based on CDC RE-AIM framework, continued engagement of stakeholders, integration and coordination of services at the state and local level, and sustainability of funding.